The current application represents the Phase 2 continuation of the Phase I NIH SBIR Grant number R43 DE12686, entitled A novel agent for the therapy of gingivitis . In the Phase I application, we have presented evidence that mercaptoethylguanidine (MEG) is a promising nitric oxide synthase (NOS) inhibitor with selectivity for the inducible nitric oxide synthase isoform (iNOS), and with an additional free radical scavenger activity, and proposed to perform pre-clinical studies in the rat to demonstrate its efficacy in periodontal disease. The studies performed in the Phase I studies confirmed iNOS expression and peroxynitrite generation in periodontitis, and demonstrated the potent antiinflammatory effects of MEG in a rat model of ligature-induced periodontitis. In the current application, we propose to inform pre-clinical studies with a MEG in order to develop it as a treatment for periodontal disease. The specific aims of the present proposal are to synthesize large quantities of MEG, and perform studies in beagle dog models of gingivitis and periodontitis in order to obtain definitive proof of principle that this agent can reduce the tissue injury and inflammation. Additional aims of the current submission are to complete the on-going pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, local irritation tests), to reach the stage of investigational drug application to the FDA, and conduct a Phase I/II human clinical trial with MEG for the treatment of gingivitis. PROPOSED COMMERCIAL APPLICATION Worldwide the market for an effective, safe pharmaceutical for periodontal diseases is estiamted to be over 20 billion dollars per year. Current market entrants are marginally effective. MEG may represent a highly potent and successful candidate therapy; funding of SBIR Phase II will allow for market entry in 3-4 years.